BY ANTHONY KING | IMAGE: ITALIAN INSTITUTE OF TECHNOLOGY
Imagine the possibilities if we could safely and routinely deploy batteries into the human body. Not just for monitoring and compliance but also for bringing some medical procedures out of the lab and into the home, Anthony King reports
In 2023, Time magazine listed among the year’s best innovations the first ever rechargeable edible battery (Adv. Mater., DOI: 10.1002/adma.202211400). The battery’s developer, Mario Caironi, an electronics engineer at the Italian Institute of Technology in Genoa, scrolled through approved food additives and ingredients to pinpoint materials suitable as insulators, conductors and semiconductors and tested the most favourable candidates.
‘If we can make electronic materials that can be digested, then we completely reduce the risk for the user and also to the environment at the end of life,’ Caironi says. And he’s not alone in seeing their potential.
US headquartered Proteus earlier developed an edible sensor, the size of a grain of sand, inside a pill to track patient compliance with schizophrenia medications. This was the first drug with an embedded sensor to be granted US FDA approval, in 2017. Once valued at over $1bn, Proteus filed for bankruptcy in 2020. Nonetheless, the technology – consisting of edible metals – raised the profile of edible electronics. Much of the research into ingestible sensors and devices is now carried out in academe. The gastrointestinal (GI) tract (photo, left) is the obvious first port of call.
‘The gut is a unique place in the body, where we don’t need implantable devices that cause worries about infections or body responses,’ says Khalil Ramadi, a bioengineer at New York University, US. Plus, there are many opportunities for digestible devices to offer health benefits in the gut. Today, when a patient swallows a camera, they must be monitored continuously by a physician and there is a small risk of the capsule getting lodged in their intestine.
At Georgia Institute of Technology, US, Alex Abramson’s lab is now developing a mm-size pill made from stainless steel and injection moulded polypropylene. Within the capsule is a tiny integrated circuit powered by silver oxide batteries. The bottom part is heavily weighted, since it is made from stainless steel, allowing the pill to orient itself so the business end of the device faces the stomach tissue. ‘A steel needle inserts into the tissue and electrical stimulation is pulsed through the needle into the muscle layer of the stomach,’ Abramson explains. The device completes its circuit within the body to ensure that the stimulation of the muscle wall alleviates symptoms of gastroparesis, which is when the stomach takes too long to empty its contents.
There is already an FDA approved device that stimulates the GI wall for such gastroparesis patients, but it must be surgically implanted. ‘We want to perform the same stimulation, but in pill form,’ says Abramson. ‘A person could take the pill to allow for stimulations to cover a defined period, say 24 hours.’ He and others – including Giovanni Traverso at Massachusetts Institute of Technology – have filed patents on the device.
The challenge has been to get the electronics small enough to fit inside the pill but also have miserly power demands. ‘The battery is actually one of the highest volume components of the pill,’ says Abramson, who also works with Yasser Khan at the University of Southern California to redesign and miniaturise integrated circuits.
A lot of medical devices are now powered by commercially available silver oxide batteries. These are used for one-time applications such as cameras for GI endoscopies but are not suitable for more frequent use, according to Christopher Bettinger, biomedical engineer at Carnegie Mellon University in Pittsburgh, Pennsylvania. ‘If you’re doing something once a day, like delivering a drug or delivering cells, that kind of compounded risk would not be very tolerable,’ he explains.
Alternatives are being investigated. Bettinger says it is best to think about power supply for specific applications. ‘We don’t need the same level of power supply as for consumer electronics and maybe it is okay if it degrades,’ he adds. Bettinger and his colleagues made headlines in 2016 with a battery cathode made from non-toxic melanin pigments, which are redox active compounds that chelate metals in our brains. Building on the idea of binding to metals, the group used 600mg of melanin as the cathode to power a 5mW device for up to 18 hours. Sodium titanium phosphate, which is also non-toxic, functioned as the anode (Adv. Materials, DOI: 10.1002/adma.201504650) This battery also had the advantage that it would be digested inside the body.
‘In principle it is good, but in practice the charge capacities aren’t big enough to move the needle and there are [commercial] risks in manufacturing new materials,’ says Bettinger. Meanwhile, researchers continue to work to reduce the energy demand from electronics for use in sensors and ingestible devices. Passive electronics, like on a credit card, are also of interest. Others too are on the hunt for not just ingestible, but edible electronics and batteries.
Smart pills
In Italy, Caironi is focused on two concepts as part of the EU-funded Electronic Food Project (ELFO, https://elfoproject.eu): electronic tags for food monitoring and smart edible pills for disease diagnosis and treatment. He has sought new food materials to make edible electronics, such as replacing silicon with natural semiconductors already present in foods. He started by looking at GRAS (generally regarded as safe) materials listed by the FDA and the European Food Safety Authority.
Many dyes and pigments in nature act as natural semiconductors, Caironi says. ‘We’ve got some nice results from carotenoids, with beta-carotene for example, as semiconductors if you process them in the right way,’ he adds. Gold is a top choice as an electrode material – some restaurants serve steak with gold leaf, so it is perfectly edible. Caironi and colleagues also reported an edible composite bilayer made from ethyl cellulose and activated carbon. Ethyl cellulose is an approved food additive often used in drugs and the food industry, while activated carbon is an edible electronic conductor that is neither absorbed nor metabolised in the gut. For their edible energy harvesting device, the cellulose acted as an insulator and the carbon as a conductor, with other food additives for stability (Nano Energy, DOI: 10.1016/j.nanoen.2023.108168).
The group also reported on a chitosan-gated organic transistor printed on ethyl cellulose (Nanoscale, DOI: 10.1039/D3NR01051A). Other researchers have highlighted the potential of starch for flexible electronics, as it is biodegradable and edible (npj Flex Electron, DOI: 10.1038/s41528-022-00147-x). A collaboration between the University of Bristol and the Italian Institute of Technology in Milan reported on a spray-on edible strain sensor comprising activated carbon as conductor, gummy bears as binder and water-ethanol mixture as dispersant. This changes resistance when compressed, so can provide feedback to an edible actuator, which turns energy into mechanical movement (Adv. Sens. Res., DOI: 10.1002/adsr.202300150).
Caironi and colleagues meanwhile drew inspiration from nature in designing their rechargeable edible battery from food. After searching for molecules that can be reversibly oxidised and reduced, they opted to immobilise riboflavin and the flavonoid compound quercetin on activated carbon. Riboflavin or vitamin B2 was used as the anode, while quercetin, found in capers and red onions, was used as the cathode.
‘By encapsulating the electrodes and a water-based electrolyte in beeswax, a fully edible battery is fabricated capable of supplying power to small electronic devices,’ the researchers report. The cell operated at 0.65V, sustaining a current of 48µA for 12 min.
Meanwhile a group at the University of Bristol designed an edible battery made from gelatin and activated charcoal; the idea was to use the carbon as an inert electrode to split water. However, ‘this is more of a fuel cell,’ says Caironi, who has collaborated with the Bristol group. ‘It doesn’t provide a stable voltage.’
Stimulating delivery
Still others see merit in working with existing materials. Bettinger’s research direction was galvanised by advances with thin silicon films made by materials scientist John Rogers at Northwestern University, US. If small enough quantities of silicon are deployed, then the metal is essentially resorbable. ‘A nanometre piece of silicon has on the order of the same number of atoms that you might eat in a meal, and there are even silicate preservatives and all sorts of weird stuff we eat every day,’ says Bettinger. ‘Silicon is like the undefeated boxer. It has many challengers, but it is still the perennial victor.’
Why tolerate the ‘really poor performances and instability of organic-based logic circuits,’ he asks, when you can back silicon.
Research soldiers on. In 2025, Caironi plans to unveil a prototype of an entirely edible electronic pill; it will include edible electronic circuits, an edible sensor and battery and a communication system that exploits the natural electrical activity and conductivity of the body.
‘You ingest the pill. The insulation is dissolved in intestinal fluid, which causes a change in resistance between the two electrodes. This modulates the signal, indicating that the drug inside the pill has been released,’ Caironi explains.
In New York, Ramadi is interested in tapping into the huge number of gut neurons as a way of tweaking hormones; hunger or metabolism; and even inflammation. In 2023, his group reported on bioinspired, ingestible electroceutical capsules for influencing hormones that regulate feelings of hunger (Sci. Robotics, doi: 10.1126/scirobotics.ade9676). It consisted of a silver oxide battery and electronics encapsulated in plastic surrounded by a thin wire. The pill delivered an electrical stimulation to the stomach for around 20 minutes ‘and we got pretty significant changes in a whole bunch of hormones associated with hunger and metabolism,’ says Ramadi.
He sees clear upsides to plugging into the huge nervous system of the gut. ‘The language of these nerves is electrical signals,’ he says. ‘Unlike chemicals, we can control electricity a lot better in terms of where it goes and when it goes. It gives you a lot more access in terms of how we deliver therapy.’
Abramson has ambitious ideas around pills harbouring micro-needles. ‘We use a timed actuator that is hydration triggered, since the stomach is at 100% humidity,’ he explains. Getting drugs into precise locations in the GI tract is difficult, but this strategy offers a way forward. ‘We could deliver mRNA therapeutics using a micro-needle injection into the tissue wall of the stomach,’ says Abramson. ‘There’s lots of interest in the gut-brain axis and neurostimulation of the gut.’ This technology could release peptides and hormones that could influence feelings of fullness and address metabolic diseases.
Others are similarly excited. ‘Maybe you can design a drug to deliver certain compounds to a specific location,’ says Bettinger. ‘There might be high value compounds or a tranche of cells you want precision-delivered in a targeted way.’ This is where sensors for pH, humidity and actuators that inject into the gut wall could play a role in smart pills for future therapies.
‘We are filing patents, but there is a long way to go in ingestible electronics,’ says Caironi. ‘Our goal is to show various applications and create a new field.’
Ramadi’s ‘electroceutical’ pills, meanwhile, were tested in pigs and he hopes to move a pill towards clinical trials within the next four to five years. ‘Realistically, people probably have access to these technologies within 10 years, but maybe it can be sooner,’ he says.
Swallowable smart pills are exciting, but there are also other sectors seeking biodegradable electronic, sensor and communication technologies. An example is agritech, which desires multiple low-cost sensors to be placed in a field to measure changes in environmental conditions. Another avenue to market is for tracking the condition and quality of foodstuffs.
The possibilities in medicine are what really excites the field, however, even if they are a little further off. Yet they are drawing ever closer. In the sci-fi film Fantastic Voyage, the shrunken submarine Proteus remains miniaturised for just 60 minutes and must get to and remove the scientist’s clot before time runs out. The real smart pills will likely begin their maiden voyages through the gut, rather than brain, but can be a fantastic addition to the armamentarium of clinicians and surgeons. That voyage is well under way.
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